Knights are among the most difficult monsters encountered later in the game. They are invincible from the front, and can only be damaged from the back or (occasionally) side, and may be a reference to Darknuts or Armos from The Legend of Zelda series, which can only be harmed in the same way.
Knights generally move about room erratically, but react to having orthogonal line-of-sight on the player. If the player gets close enough to a Knight on a horizontal or vertical path, the Knight will change direction to move towards the player. The Knight will be set in this new direction until it hits an obstacle. This means that attracting a Knight's attention, and then quickly moving behind it to shoot can be a viable strategy, especially with a high move speed and when done horizontally in rooms with few obstacles. The Knight's line of sight is limited, however, which can allow the player to shoot a Knight vertically across the room without the Knight changing direction if on opposite ends. Care should be used in fighting large numbers of them, especially in the more mazelike room layouts.
Knights can be safely dispatched with the use of piercing shots from Cupid's Arrow, Technology, or Brimstone, as these will damage them even from the front. The player can also use Bombs, or if the The Ladder or flight ability (from Lord Of The Pit or Transcendence ) is available, simply hiding safely over a pit and shooting from a distance. Knights will also take damage from walking into Fireplaces or Spikes. Status effect arrows, such as the Mutant Spider, poison or The Common Cold can be applied from the front. You can also hold Mom's Knife to kill Knights, if you're not worried about taking damage.
Using Mom's Pad will sometimes reverse the hit spot on the Knights meaning the player has to fire at the Metal face on the Knight whereas the brain seems to react like it is the Metal face.
The Selfless Knight appears in Sheol and as a champion in The Depths/Necropolis and The Womb/Utero, in which case it will drop an item when defeated. They are very, very rare enemies in The Caves/Catacombs. These Knights have a mouth wide agape similar to a Maw's expression and Isaac's face on the back of their heads. They behave just like regular Knights, except they advance towards the player at a higher speed if detected. If you were killed by knights and respawn by Guppy (9 lives) or 1up and come back to that knights room one of them will transform to Alternates.